Project IV is new and based on novel cell and transgenic (Tg) mouse models of alpha-synuclein (a-syn) Lewy bodies (LBs) and neurites (LNs) which we hypothesize mediate neurodegeneration in Parkinson's disease without (PD) and with dementia (PDD) as well as in dementia with LBs (DLB). Project IV examines mechanisms of pathological a-syn transmission in the human A53T a-syn Tg mice (M83 line) that model LB disease (LBD)-like a-syn pathology, and assesses the efficacy of passive immunotherapy to abrogate transmission of a-syn pathologies. Project III has defined two stains (A and B) of a-syn pre-formed fibrils (PFFs), and injections of strain A a-syn PFFs into striatum and cortex of young human M83 mice accelerated the widespread formation of LBs/LNs as well as onset of neurological symptoms, and this was associated with a dramatic reduction in the lifespan of injected M83 mice. The propagation of pathologic a-syn to widespread central nervous system (CNS) regions is consistent with transynaptic cell-to-cell passage of a-syn pathology. Injections of brain lysates containing pathological a-syn from 12-14 month old diseased M83 mice into young disease free M83 mice also had the same effects as synthetic a-syn PFFs indicating that a-syn PFFs alone induce PD-like pathology and transmit disease. These findings open up new avenues for understanding the progression of PD/PDD/DLB and provide fresh opportunities to develop novel therapies for LBD. Project IV aligns with the overall theme of the Penn Udall Center and collaborates with all Cores/Projects to elucidate mechanisms underlying the progression of LBD to dementia. The overarching hypothesis to be tested here is that different pathological species or strains of a-syn generated synthetically or isolated from different postmortem brain regions of PD/PDD/DLB patients transmit disease in distinct ways that reflect intrinsic properties of the different pathological a-syn strains. To that end, the Specific Aims of Project IV are: Aim 1: To determine if synthetic a-syn PFF strains A and B characterized by Project III differentially transmit LBD following injections into the brains of M83 mice using methods to assess the behavior, neuropathology and cerebrospinal fluid (CSF) levels of a-syn; Aim 2: To determine if lysates enriched in LBs/LNs from PD substantia nigra versus PDD/DLB cingulate cortex contain different a-syn strains that differentially transmit LBD following injections into the brains of M83 mice using the same methods as in Aim 1; Aim 3: To conduct proof of concept (POC) studies in M83 mice injected with pathological a-syn to determine if passive immunization with epitope specific anti-a-syn monoclonal antibodies identified by Project III to neutralize a-syn transmission, will abrogate induction and spread of a-syn pathology in vivo.